Process for the production of alpha-tocotrienol and derivatives

ABSTRACT

The invention discloses novel processes for production, enrichment and/or isolation of alpha-tocotrienol from source material comprising at least one non-alpha-tocotrienol, such as natural extracts comprising mixed tocotrienols.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. provisional patentapplication No. 61/197,585, filed Oct. 28, 2008. The content of thatapplication is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This invention relates generally to a process for production, enrichmentand/or isolation of pure alpha-tocotrienol from natural extracts thatcomprise mixed tocols. In particular, the invention relates to a noveland effective process for production, enrichment and/or isolation ofalpha-tocotrienol of high purity from plant extracts, e.g. palm oilextract such as Tocomin®, that is economically feasible on a commercialscale. The invention also relates to a process for the synthesis ofalpha-tocotrienol quinone of high purity. The invention also relates tothe alpha-tocotrienol-containing product produced by the process.

BACKGROUND OF THE INVENTION

The present invention provides a process for the production, enrichmentand/or isolation of pure alpha-tocotrienol enriched tocotrienolcompositions from naturally occurring extracts, and to thealpha-tocotrienol-containing product produced by the process. Thisprocess can be performed without chromatography, or with minimal use ofchromatography, and is economically feasible on a commercial scale.

Tocopherols and tocotrienols are molecules characterized by a6-chromanol ring structure and a side chain at the C-2-position.Tocotrienols possess a 4′, 8′, 12′ trimethyltridecyl unsaturated phytolside chain with the presence of double bonds at 3′, 7′, and 11′positions of the side chain, while tocopherols have a saturated sidechain. The geometry of each of these double bond sites is trans (alsoreferred to as E) in all four natural tocotrienols. There are fournaturally occurring tocotrienols, d-alpha-, d-beta-, d-gamma-, andd-delta-tocotrienol. The four naturally occurring tocotrienols have the(R) absolute configuration at the C-2 chroman ring position.

R¹ R² R³ Alpha- tocotrienol

methyl methyl methyl Beta- tocotrienol

methyl H methyl Gamma- tocotrienol

H methyl methyl Delta- tocotrienol

H H methyl Alpha- tocopherol

methyl methyl methyl Beta- tocopherol

methyl H methyl Gamma- tocopherol

H methyl methyl Delta- tocopherol

H H methyl

Tocotrienols are present in the oils, seeds, and other parts of manyplants used as foods (see pp. 99-165 in L. Machlin, ed., “Vitamin E: AComprehensive Treatise” for a discussion of the occurrence oftocotrienols in foods). Tocotrienol-containing concentrates can beprepared from certain plant oils and plant oil by-products such as ricebran oil or palm oil distillate. For examples of such isolationprocesses, see for instance A. G. Top et al., U.S. Pat. No. 5,190,618(1993) or Tanaka, Y. et al., Japanese Patent No. JP2003-171376 (2003).

There is a problem inherent in obtaining tocotrienols from naturalsources, in that the tocotrienol yield from such processes is a mixtureof varying amounts of all of the natural tocotrienols and tocopherols.In order to obtain a pure member of the tocotrienol family, it has beennecessary to resort to very expensive procedures such as preparativescale reverse-phase chromatography or simulated moving bedchromatography. For an example of such a purification process, see M.Kitano et al., Japanese Patent No. 2003-02777 (2003) or Burger et al.,U.S. Pat. No. 4,603,142.

The synthesis of tocotrienols in the natural form, having the (2R)chiral configuration and trans double bonding at the proper locations inthe side chain, has also been proven to be of considerable difficulty.

Syntheses of various members of the tocotrienol family in the d,l- or(RS)-form have been published; see for example Schudel et al., Helv.Chim. Acta (1963) 46, 2517 2526; H. Mayer et al., Helv. Chim. Acta(1967) 50, 1376 11393; H.-J. Kabbe et al., Synthesis (1978), 888 889; M.Kajiwara et al., Heterocycles (1980) 14, 1995 1998; S. Urano et al.,Chem. Pharm. Bull. (1983) 31, 4341 4345, Pearce et al., J. Med Chem.(1992), 35, 3595 3606 and Pearce et al., J. Med Chem. (1994). 37, 526541. None of these reported processes lead to the natural form of thetocotrienols, but rather produce racemic mixtures. Syntheses of naturalform d-tocotrienols have been published. See for example, J. Scott etal., Helv. Chim. Acta (1976) 59, 290 306, Sato et al. (Japanese Patent63063674); Sato et al. (Japanese Patent No. JP 01233278) and Couladouroset al (U.S. Pat. No. 7,038,067).

Tocotrienols occur largely in palm oil, rice bran oil, and barley. Whilesynthetic and natural tocopherols are readily available in the market,the supply of natural tocotrienols is limited, and generally comprises amixture of tocotrienols. Crude palm oil which is rich in tocotrienols(800-1500 ppm) offers a potential source of natural tocotrienols.Carotech, located in Malaysia, is an industrial plant able to extractand concentrate tocotrienols from crude palm oil. Carotech uses amolecular distillation process (employing ultra-high vacuum and very lowtemperature) in its production plant. This process (see U.S. Pat. No.5,157,132) allows Carotech to extract phytonutrients such as theTocotrienol Complex (Tocomin®, a registered trademark of Carotech forextracts and concentrates of palm tree fruits) from the crude palm oil.Tocomin®-50 typically comprises about 25.32% mixed tocotrienols (7.00%alpha-tocotrienol, 14.42% gamma tocotrienol, 3.30% delta tocotrienol and0.6% beta tocotrienol), 6.90% alpha-tocopherol and other phytonutrientssuch as plant squalene, phytosterols, co-enzyme Q10 and mixedcarotenoids.

Additional commercially available products that may be used in thepresent invention are for example, Nu Triene Tocotrienol® (30% content,a product of Eastman Chemical Company), various Oryza® tocotrienolproducts of different tocotrienol concentrations from Oryza Oil & FatCo. Ltd including Oryza tocotrienol-70 with 70% totaltocopherol/tocotrienol content, and a total tocotrienol content of 40%including 14% of alpha-tocotrienol and 24% gamma-tocotrienol, and Oryzatocotrienol-90 with 90% total tocopherol/tocotrienol content and a totaltocotrienol content of 60%; Golden Hope Plantations Berhad Tocotrienoloil (70% content), Davos Life Science TRF (63% content), Ginnoway™tocotrienol concentrate from palm and rice oil from Beijing GingkoGroup, Gold Trie® a product of Sime Darby Biorganic Sdn Bhd and PalmNutraceuticals Sdn Bhd (89% content). Delta Tocotrienol-92® (92% pure byHPLC) is a commercially available product from Beijing Gingko Group thatmay be also used in the present invention.

Methods for isolation or enrichment of tocotrienol from certain plantoils and plant oil by-products have been described in the literature,but these methods generally produce mixtures of natural tocols invarying amounts and are not economically feasible on a commercial scale.As mentioned above, in order to obtain a pure member of the tocotrienolfamily, it has been necessary to resort to expensive procedures such aspreparative scale reversed-phase chromatography or simulated moving bedchromatography. For some examples of such isolation and purificationprocesses, see for instance Top A. G. et. al., U.S. Pat. No. 5,190,618;Lane R et al., U.S. Pat. No. 6,239,171; Bellafiore, L. et al U.S. Pat.No. 6,395,915; May, C. Y et al., U.S. Pat. No. 6,656,358; Jacobs, L etal, U.S. Pat. No. 6,838,104; Sumner, C et al. Int. Pat. Pub. WO99/38860, or Jacobs, L. Int. Pat. Pub. WO 02/500054.

Production of d-alpha tocopherol from natural plant sources has beendescribed in U.S. Pat. No. 4,977,282, where natural plant sources havingVitamin E activity of a concentrate of mixed tocopherols that mightinclude tocotrienols are transformed into alpha-tocopherol. In thisisolation, alpha tocopherol is enriched after amino-alkylating the mixedtocopherols which are then reduced by catalytic hydrogenation to convertthe mixture of the non-alpha tocopherol tocols into alpha-tocopherol. Inthis process, any tocotrienols present would be hydrogenated totocopherol. See Netscher et al. (2007) Eur J. Org. Chem 1176-1183

Because of the similar molecular and retention characteristics of thevarious individual tocopherols and tocotrienols, separation of theindividual compounds has been proven difficult and not commerciallyviable. Although the process for the production of alpha-tocotrienol hasbeen described, it is only available in pure form at very high prices(e.g., USD$672 for 100 mg of ≥98% pure alpha-tocotrienol from FlukaChemical Company in October, 2009).

In light of the above, there remains a need for a method of producingthe naturally occurring alpha-tocotrienol in a pure form that iseconomically feasible on a commercial scale. Such a process wouldminimize the number of processing steps required, and would not require,or would minimize the use of, chromatographic separations.

DISCLOSURE OF THE INVENTION

In accordance with the purposes of this invention, in one aspect, thisinvention relates to a novel process for the production, enrichment,and/or isolation of alpha-tocotrienol from source material comprising atleast one tocotrienol which is not alpha-tocotrienol. In someembodiments, the at least one tocotrienol which is not alpha-tocotrienolcomprises beta-tocotrienol, gamma-tocotrienol, or delta-tocotrienol; orany two of beta-tocotrienol, gamma-tocotrienol, or delta-tocotrienol; orall three of beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol.In any of the foregoing embodiments, the source material can optionallyalso comprise alpha tocopherol. In one embodiment, this inventionrelates to a novel process for the production, enrichment and/orisolation of pure alpha-tocotrienol from plant extracts comprisingnaturally occurring mixed tocotrienols. In one embodiment, thisinvention relates to a novel process for the production, enrichmentand/or isolation of pure alpha-tocotrienol from plant extracts enrichedin naturally occurring mixed tocotrienols. In one embodiment theinvention does not need the use of chromatography, and is amenable tolarge commercial production of alpha-tocotrienol. In another embodimentthe invention needs minimal use of chromatography and is amenable tolarge commercial production of alpha-tocotrienol

In one embodiment, the invention relates to a novel process for theproduction, enrichment and/or isolation of pure alpha-tocotrienol fromnaturally occurring extracts comprising a mixture of tocotrienols andalpha tocopherol. In another embodiment, the naturally occurring extractis a palm oil extract, a palm fruit extract, or a palm oil/palm fruitextract. In another embodiment, the naturally occurring extract is apalm oil extract, a palm fruit extract, or a palm oil/palm fruit extractwhich has been concentrated. In another embodiment, the naturallyoccurring extract is a palm oil extract, a palm fruit extract, or a palmoil/palm fruit extract from Elaeis guineensis. In another embodiment,the naturally occurring extract is a palm oil extract a palm fruitextract, or a palm oil/palm fruit extract from Elaeis guineensis whichhas been concentrated. In another embodiment, the naturally occurringextract is the commercial palm oil concentrate Tocomin®, a product ofCarotech Bhd. (Malaysia), which comprises a mixture of tocotrienols andalpha-tocopherol extracted and concentrated from virgin crude palmoil/palm fruits (Elaeis guineensis) and which also includes non-tocolphytonutrients such as plant squalene, phytosterols, co-enzyme Q10 andmixed carotenoids that are naturally extracted together withtocotrienols from palm fruits. In some embodiments, the naturallyoccurring extract is an extract of palm oil, rice bran oil, barley orannatto, or any combination of two or more of the foregoing oils. Inanother embodiment the formulation of the present invention comprises anenriched tocotrienol extract from palm oil, as sold by Carotech, GoldenHope Bioorganic, Davos Life Science, Beijing Gingko Group, Eisai,Eastman Corporation, Sime Darby Biorganic Sdn Bhd or PalmNutraceuticals.

Another embodiment of the invention comprises the production, enrichmentand/or isolation of natural d-alpha-tocotrienol from a materialcomprising at least one compound selected from:

reacting said material with a formaldehyde equivalent and at least oneamine compound of the formula H—N(R₁₁)(R₁₂), where R₁₁ and R₁₂ areindependently selected from the group consisting of H and C₁-C₈ alkyl,or where R₁₁ and R₁₂ are combined together with the nitrogen to whichthey are bonded to form a five-to-eight membered heterocyclic ring, saidheterocyclic ring having zero, one, or two additional heteroatoms inaddition to the nitrogen to which R₁₁ and R₁₂ are bonded, to produce atleast one aminomethylated compound selected from:

separating the aminomethylated compound or compounds fromnon-aminomethylated compounds, and reducing the aminomethylated compoundor compounds to yield

One embodiment of the invention, as described in FIG. 1, comprises theproduction, enrichment and/or isolation of natural d-alpha-tocotrienolfrom natural plant sources that comprise at least one non-alphatocotrienol, and optionally additional tocotrienols, and that optionallyalso include alpha tocopherol and optionally other tocols and optionallynon-tocol phytonutrients or impurities, comprising the steps of:

1a.) reacting a plant extract mixture with suitable reagents which willreact with the one or more non-alpha-tocols to introduce a functionalgroup in the free 5 and/or 7 positions of the one or morenon-alpha-tocols;

1b.) separating the one or more non-alpha-tocols homologues that havebeen functionalized, from the alpha-tocotrienol, the optional alphatocopherol and other non-tocol compounds that may be present;

1c.) optionally further separating the alpha-tocotrienol in the mixtureseparated in step (1b), from the optional alpha tocopherol and othernon-tocol compounds;

1d.) chemically reacting the one or more non-alpha-tocol functionalizedhomologues from step (1b) to give alpha-tocotrienol; and

1e.) optionally combining the alpha-tocotrienol from step (1c) with thenewly produced alpha-tocotrienol from step (1d) to givealpha-tocotrienol of high purity.

In another embodiment, step 1b) is followed by an optional step 1b1) offiltering a solution of the one or more non-alpha-tocols homologues thathave been functionalized. Filtration can be performed using diatomaceousearth such as Celite® or any other method of filtration known to theskilled artisan.

In another embodiment, step 1d) is followed by an optional step 1d1),wherein a solution of the alpha-tocotrienol (in a solvent such astoluene) produced by the reduction is mixed with silica gel. The silicagel is removed by filtration, and the remaining filtrate is concentratedto give alpha-tocotrienol of high purity.

In another embodiment, both steps 1b1) and 1d1) are performed.

In another embodiment, the plant extract is a palm oil plant extract. Inanother embodiment, the plant extract is a palm fruit plant extract. Inanother embodiment, the plant extract is a rice extract. In anotherembodiment, the plant extract is a rice bran oil extract. In anotherembodiment, the plant extract is a barley extract. In anotherembodiment, the plant extract is an annatto extract. In anotherembodiment, the plant extract is a mixture of two or more of theforegoing plant extracts.

In one embodiment, introduction of a functional group in the free 5and/or 7 positions of the non-alpha tocol homologues comprisesintroduction of a group which provides for increased differentialsolubility of the functionalized non-alpha tocol homologues compared tonon-functionalized compounds in the starting material, source material,or extract. The increased differential solubility can be differentialsolubility in a single solvent, or increased differential solubilitybetween two or more solvents in a mixed solvent system. In oneembodiment, the introduction of a functional group in the free 5 and/or7 positions of the non-alpha tocol homologues is accomplished withoutreducing the double bonds present in tocotrienol compounds and/orwithout causing isomerization of the double bonds present in tocotrienolcompounds. In one embodiment, the step of chemically reacting thenon-alpha tocol functionalized homologues to produce alpha-tocotrienolis accomplished without reducing the double bonds present in tocotrienolcompounds and/or without causing isomerization of the double bondspresent in tocotrienol compounds.

In one embodiment, the functionalization is introduced byamino-alkylation followed by acidification, thus converting thenon-alpha-tocotrienol into the corresponding amino-alkylated product andconverting said products to acid salts. In some embodiments, thefunctionalization is introduced by amino-alkylation with a formaldehydeequivalent, such as paraformaldehyde, and an amine, such as a secondaryamine, such as a cyclic amine such as 1-methylpiperazine, piperidine ormorpholine. In some embodiments, the functionalization is introduced byamino-alkylation with paraformaldehyde and 1-methylpiperazine. In someembodiments, the functionalization is introduced by amino-alkylationwith paraformaldehyde and morpholine.

In one embodiment, the separation of the amino-alkylation products fromthe alpha-tocotrienol, the optional alpha tocopherol and other non-tocolcompounds that may be present is done by partitioning between twoorganic layers. In one embodiment, the separation of theamino-alkylation products from the alpha-tocotrienol, the optional alphatocopherol and other non-tocol compounds that may be present is done bypartitioning between an organic layer and an aqueous layer. In oneembodiment, the separation of the amino-alkylation products from thealpha-tocotrienol, the optional alpha tocopherol and other non-tocolcompounds that may be present is done by partitioning using an acidicorganic layer such as acetonitrile comprising formic acid.

In another embodiment, the non-alpha-tocotrienol functionalizedhomologues are reduced with a hydride reagent such as sodium cyanoborohydride (NaCNBH₃). In another embodiment, the non-alpha-tocotrienolfunctionalized homologues are reduced with a hydride reagent such assodium borohydride. In another embodiment, the non-alpha-tocotrienolfunctionalized homologues are reduced with lithium borohydride, zincborohydride, or tetraalkylammonium hydride. In yet another embodiment,the non-alpha-tocotrienol functionalized homologues are reduced with ahydride reagent such as lithium aluminum hydride. In yet anotherembodiment, the non-alpha-tocotrienol functionalized homologues arereduced with a borane, diborane, or a borane complex, such asborane-t-butyl amine complex. In another embodiment, thenon-alpha-tocotrienol functionalized homologues are reducedelectrochemically or with an electron donor such as sodium, lithium,magnesium, potassium, zinc, nickel, or amalgams thereof, in the presenceof a suitable proton source such as ammonium salts or carboxylic acids.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol of high purity. In some embodiments, the purityis in the range of 80% to 99.9%, or in the range of 85% to 99.9%, or inthe range of 90% to 99.9%, or in the range of 95% to 99.9%. In someembodiments, the purity is in the range of about 80% to about 99.9%, orin the range of about 85% to about 99.9%, or in the range of about 90%to about 99.9%, or in the range of about 95% to about 99.9%. In someembodiments, the purity is more than 80%, or more than 85%, or more than90%, or more than 91%, or more than 92%, or more than 93%, or more than94%, or more than 95%, or more than 96%, or more than 97%, or more than98%, or more than 99%, or more than 99.5%, or more than 99.9%. In someembodiments, the purity is more than about 80%, or more than about 85%,or more than about 90%, or more than about 91%, or more than about 92%,or more than about 93%, or more than about 94%, or more than about 95%,or more than about 96%, or more than about 97%, or more than about 98%,or more than about 99%, or more than about 99.5%, or more than about99.9%. In other embodiments, the impurities in the final product areless than 20%, or less than 15%, or less than 10%, or less than 5%, orless than 4%, or less than 3%, or less than 2%, or less than 1%, or lessthan 0.5%, or less than 0.1%. In other embodiments, the impurities inthe final product are less than about 20%, or less than about 15%, orless than about 10%, or less than about 5%, or less than about 4%, orless than about 3%, or less than about 2%, or less than about 1%, orless than about 0.5%, or less than about 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5% or less than 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than about 5%, less than about 4%, less than about 3%,less than about 2%, less than about 1%, less than about 0.5% or lessthan about 0.1%. In one embodiment, the invention provides a method forlarge-scale production, enrichment, and/or isolation ofalpha-tocotrienol, such as quantities of material containingalpha-tocotrienol of at least 50 grams, at least 100 grams, at least 250grams, at least 500 grams, at least 1 kilogram, at least 2 kilograms, atleast 5 kilograms, or at least 10 kilograms, or at least about 50 grams,at least about 100 grams, at least about 250 grams, at least about 500grams, at least about 1 kilogram, at least about 2 kilograms, at leastabout 5 kilograms, or at least about 10 kilograms. The quantity ofmaterial containing alpha-tocotrienol can have any purity level asrecited herein.

In some of the above mentioned embodiments, the process involves anadditional optional step, wherein the alpha-tocotrienol of high purityis oxidized to produce alpha-tocotrienol quinone of high purity. In oneembodiment, the conversion of alpha-tocotrienol to alpha-tocotrienolquinone is carried out under buffered conditions. In one embodiment, thebuffer and/or base employed during conversion of alpha-tocotrienol toalpha-tocotrienol quinone is sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogen carbonate, phosphatebuffer, or any mixture in any proportion of two or more of the foregoingbuffers.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol quinone of high purity. In some embodiments, thepurity is in the range of 80% to 99.9%, or in the range of 85% to 99.9%,or in the range of 90% to 99.9%, or in the range of 95% to 99.9%. Insome embodiments, the purity is in the range of about 80% to about99.9%, or in the range of about 85% to about 99.9%, or in the range ofabout 90% to about 99.9%, or in the range of about 95% to about 99.9%.In some embodiments, the purity is more than 80%, or more than 85%, ormore than 90%, or more than 91%, or more than 92%, or more than 93%, ormore than 94%, or more than 95%, or more than 96%, or more than 97%, ormore than 98%, or more than 99%, or more than 99.5%, or more than 99.9%.In some embodiments, the purity is more than about 80%, or more thanabout 85%, or more than about 90%, or more than about 91%, or more thanabout 92%, or more than about 93%, or more than about 94%, or more thanabout 95%, or more than about 96%, or more than about 97%, or more thanabout 98%, or more than about 99%, or more than about 99.5%, or morethan about 09.9%. In other embodiments, the impurities in the finalproduct are less than 20%, or less than 15%, or less than 10%, or lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1%, or less than 0.5%, or less than 0.1%. In other embodiments, theimpurities in the final product are less than about 20%, or less thanabout 15%, or less than about 10%, or less than about 5%, or less thanabout 4%, or less than about 3%, or less than about 2%, or less thanabout 1%, or less than about 0.5%, or less than about 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than 5%, less than 4%, less than 3%, lessthan 2%, less than 1%, less than 0.5% or less than 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than about 5%, less than about 4%, less thanabout 3%, less than about 2%, less than about 1%, less than about 0.5%or less than about 0.1%. In one embodiment, the invention provides amethod for large-scale production, enrichment and/or isolation ofalpha-tocotrienol quinone, such as quantities of material containingalpha-tocotrienol quinone of at least 50 grams, at least 100 grams, atleast 250 grams, at least 500 grams, at least 1 kilogram, at least 2kilograms, at least 5 kilograms, or at least 10 kilograms, or at leastabout 50 grams, at least about 100 grams, at least about 250 grams, atleast about 500 grams, at least about 1 kilogram, at least about 2kilograms, at least about 5 kilograms, or at least about 10 kilograms.The quantity of material containing alpha-tocotrienol quinone can haveany purity level as recited herein.

In another embodiment, the invention comprises a method for oxidizingalpha-tocotrienol to alpha-tocotrienol quinone with minimalisomerization of the double bonds of the triene moiety. In someembodiments, the alpha-tocotrienol quinone,2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione,produced by the method comprises at least about 80%, at least about 90%,at least about 95%, at least about 96%, at least about 97%, at leastabout 98%, at least about 99%, at least about 99.5%, or at least about99.9% of the2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dionematerial present.

In any of the above embodiments, the oxidation of alpha-tocotrienol toalpha-tocotrienol quinone can be performed with cerium (IV) ammoniumnitrate.

In another embodiment, a solution of alpha-tocotrienol quinone, in asolvent such as isopropylacetate, n-heptane, or a mixture ofisopropylacetate and n-heptane, is placed on a chromatography columnpacked with silica gel. The silica gel can contain between about 0.1-5%by weight of sodium hydrogen carbonate, such as about 0.5-2% by weightor about 1% by weight of sodium hydrogen carbonate. Thealpha-tocotrienol quinone can be eluted from the silica gel/NaHCO₃ withsolvents, such as n-heptane, isopropylacetate, orn-heptane:isopropylacetate in ratios of about 100:1, about 100:5, about100:10, or about 100:15. The recovered solution of alpha-tocotrienolquinone can be concentrated to give alpha-tocotrienol quinone of highpurity.

In another embodiment the foregoing quantities of alpha-tocotrienol oralpha-tocotrienol quinone can be produced using a single performance ofthe method, that is, with a single iteration of the steps of the method.

One embodiment of the invention, as described in FIG. 2, comprises theproduction, enrichment and/or isolation of natural d-alpha-tocotrienolfrom a natural plant source extract from palm oil, wherein said extractcomposes at least one non-alpha tocotrienol, comprising the steps of:

2a.) reacting a palm oil extract mixture with amino-alkylating agentswhich will react with the one or more non-alpha-tocols to introduce afunctional group in the free 5 and/or 7 positions of the one or morenon-alpha-tocotrienols and converting the products into acid salts,

2b.) separating the one or more non-alpha-tocotrienol acid salts of theproducts from step (2a), from the alpha-tocotrienol, optional alphatocopherol and other non-tocol compounds that may be present; and

2c.) reducing the non-alpha-tocotrienol functionalized homologues with areducing agent to give alpha-tocotrienol of high purity.

In this particular embodiment, the alpha-tocotrienol separated from theone or more amino-alkyl tocotrienol homologues in step (2b) is notrecovered, thus allowing for a process yielding pure alpha-tocotrienolwithout the need of intensive and/or expensive chromatography.

In another embodiment, the process does not comprise an additional stepwherein the alpha-tocotrienol from step (2b) is recovered, thus allowingfor a more economical commercial process.

In another embodiment, step 2b) is followed by an optional step 2b1) offiltering a solution of the one or more non-alpha-tocols homologues thathave been functionalized. Filtration can be performed using diatomaceousearth such as Celite® or any other method of filtration known to theskilled artisan.

In another embodiment, step 2c) is followed by an optional step 2c1),wherein a solution of the alpha-tocotrienol (in a solvent such astoluene) produced by the reduction is mixed with silica gel. The silicagel is removed by filtration, and the remaining filtrate is concentratedto give alpha-tocotrienol of high purity.

In another embodiment, both step 2b1) and 2c1) are performed.

In one embodiment, the palm oil extract is commercially availableTocomin®. In another embodiments the palm oil extract is commerciallyavailable Tocomin®-50.

In one embodiment, introduction of an aminoalkyl group in the free 5and/or 7 positions of the non-alpha tocol homologues provides forincreased differential solubility of the functionalized non-alpha tocolhomologues compared to non-functionalized compounds in the startingmaterial, source material, or extract. The increased differentialsolubility can be differential solubility in a single solvent, orincreased differential solubility between two or more solvents in amixed solvent system. In one embodiment, the introduction of anaminoalkyl group in the free 5 and/or 7 positions of the non-alpha tocolhomologues is accomplished without reducing the double bonds present intocotrienol compounds and/or without causing isomerization of the doublebonds present in tocotrienol compounds. In one embodiment, the step ofreducing the non-alpha tocol functionalized homologues to producealpha-tocotrienol is accomplished without reducing the double bondspresent in tocotrienol compounds and/or without causing isomerization ofthe double bonds present in tocotrienol compounds.

In another embodiment, the amino-alkylation is performed with aformaldehyde equivalent, such as paraformaldehyde, and an amine, such asa secondary amine, such as a cyclic amine selected from1-methylpiperazine, piperidine or morpholine. In yet another embodimentthe amino-alkylation is performed with paraformaldehyde and1-methylpiperazine. In yet another embodiment, the amino-alkylation isperformed with paraformaldehyde and morpholine.

In another embodiment, the reduction is performed with a hydride reagentsuch as lithium aluminum hydride, lithium borohydride, zinc borohydride,tetraalkylammonium hydride, sodium borohydride or sodium cyanoborohydride.

In another embodiment, the reduction is performed with a borane,diborane, or a borane complex, such as borane t-butyl amine complex.

In another embodiment, the reduction is performed electrochemically orwith an electron donor such as sodium, lithium, potassium, magnesium,zinc or nickel or amalgams thereof in the presence of a suitable protonsource, such as a protic solvent such as an organic alcohol or liquidammonia, or such as ammonium salts or carboxylic acids.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol of high purity. In some embodiments, the purityis in the range of 80% to 99.9%, or in the range of 85% to 99.9%, or inthe range of 90% to 99.9%, or in the range of 95% to 99.9%. In someembodiments, the purity is in the range of about 80% to about 99.9%, orin the range of about 85% to about 99.9%, or in the range of about 90%to about 99.9%, or in the range of about 95% to about 99.9%. In someembodiments, the purity is more than 80%, or more than 85%, or more than90%, or more than 91%, or more than 92%, or more than 93%, or more than94%, or more than 95%, or more than 96%, or more than 97%, or more than98%, or more than 99%, or more than 99.5%, or more than 99.9%. In someembodiments, the purity is more than about 80%, or more than about 85%,or more than about 90%, or more than about 91%, or more than about 92%,or more than about 93%, or more than about 94%, or more than about 95%,or more than about 96%, or more than about 97%, or more than about 98%,or more than about 99%, or more than about 99.5%, or more than about99.9%. In other embodiments, the impurities in the final product areless than 20%, or less than 15%, or less than 10%, or less than 5%, orless than 4%, or less than 3%, or less than 2%, or less than 1%, or lessthan 0.5%, or less than 0.1%. In other embodiments, the impurities inthe final product are less than about 20%, or less than about 15%, orless than about 10%, or less than about 5%, or less than about 4%, orless than about 3%, or less than about 2%, or less than about 1%, orless than about 0.5%, or less than about 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5% or less than 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than about 5%, less than about 4%, less than about 3%,less than about 2%, less than about 1%, less than about 0.5% or lessthan about 0.1%. In one embodiment, the invention provides a method forlarge-scale production, enrichment, and/or isolation ofalpha-tocotrienol, such as quantities of material containingalpha-tocotrienol of at least 50 grams, at least 100 grams, at least 250grams, at least 500 grams, at least 1 kilogram, at least 2 kilograms, atleast 5 kilograms, or at least 10 kilograms, or at least about 50 grams,at least about 100 grams, at least about 250 grams, at least about 500grams, at least about 1 kilogram, at least about 2 kilograms, at leastabout 5 kilograms, or at least about 10 kilograms. The quantity ofmaterial containing alpha-tocotrienol can have any purity level asrecited herein.

In some of the above mentioned embodiments, the process involves anadditional optional step, wherein the alpha-tocotrienol of high purityis oxidized to produce alpha-tocotrienol quinone of high purity. In oneembodiment, the conversion of alpha-tocotrienol to alpha-tocotrienolquinone is carried out under buffered conditions. In one embodiment, thebuffer and/or base employed during conversion of alpha-tocotrienol toalpha-tocotrienol quinone is sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogen carbonate, phosphatebuffer, or any mixture in any proportion of two or more of the foregoingbuffers.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol quinone of high purity. In some embodiments, thepurity is in the range of 80% to 99.9%, or in the range of 85% to 99.9%,or in the range of 90% to 99.9%, or in the range of 95% to 99.9%. Insome embodiments, the purity is in the range of about 80% to about99.9%, or in the range of about 85% to about 99.9%, or in the range ofabout 90% to about 99.9%, or in the range of about 95% to about 99.9%.In some embodiments, the purity is more than 80%, or more than 85%, ormore than 90%, or more than 91%, or more than 92%, or more than 93%, ormore than 94%, or more than 95%, or more than 96%, or more than 97%, ormore than 98%, or more than 99%, or more than 99.5%, or more than 99.9%.In some embodiments, the purity is more than about 80%, or more thanabout 85%, or more than about 90%, or more than about 91%, or more thanabout 92%, or more than about 93%, or more than about 94%, or more thanabout 95%, or more than about 96%, or more than about 97%, or more thanabout 98%, or more than about 99%, or more than about 99.5%, or morethan about 99.9%. In other embodiments, the impurities in the finalproduct are less than 20%, or less than 15%, or less than 10%, or lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1%, or less than 0.5%, or less than 0.1%. In other embodiments, theimpurities in the final product are less than about 20%, or less thanabout 15%, or less than about 10%, or less than about 5%, or less thanabout 4%, or less than about 3%, or less than about 2%, or less thanabout 1%, or less than about 0.5%, or less than about 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than 5%, less than 4%, less than 3%, lessthan 2%, less than 1%, less than 0.5% or less than 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than about 5%, less than about 4%, less thanabout 3%, less than about 2%, less than about 1%, less than about 0.5%or less than about 0.1%. In one embodiment, the invention provides amethod for large-scale production, enrichment, and/or isolation ofalpha-tocotrienol quinone, such as quantities of material containingalpha-tocotrienol quinone of at least 50 grams, at least 100 grams, atleast 250 grams, at least 500 grams, at least 1 kilogram, at least 2kilograms, at least 5 kilograms, or at least 10 kilograms, or at leastabout 50 grams, at least about 100 grams, at least about 250 grams, atleast about 500 grams, at least about 1 kilogram, at least about 2kilograms, at least about 5 kilograms, or at least about 10 kilograms.The quantity of material containing alpha-tocotrienol quinone can haveany purity level as recited herein.

In another embodiment, the invention comprises a method for oxidizingalpha-tocotrienol to alpha-tocotrienol quinone with minimalisomerization of the double bonds of the triene moiety. In someembodiments, the alpha-tocotrienol quinone,2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione,produced by the method comprises at least about 80%, at least shoot 90%,at least about 95%, at least about 96%, at least about 97%, at leastabout 98%, at least about 99%, at least about 99.5%, or at least about99.9% of the2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dionematerial present.

In any of the above embodiments, the oxidation of alpha-tocotrienol toalpha-tocotrienol quinone can be performed with cerium (IV) ammoniumnitrate.

In another embodiment, a solution of alpha-tocotrienol quinone, in asolvent such as isopropylacetate, n-heptane, or a mixture ofisopropylacetate and n-heptane, is placed on a chromatography columnpacked with silica gel. The silica gel can contain between about 0.1-5%by weight of sodium hydrogen carbonate, such as about 0.5-2% by weightor about 1% by weight of sodium hydrogen carbonate. Thealpha-tocotrienol quinone can be eluted from the silica gel/NaHCO₃ withsolvents, such as n-heptane, isopropylacetate, orn-heptane:isopropylacetate in ratios of about 100:1, about 100:5, about100:10, or about 100:15. The recovered solution of alpha-tocotrienolquinone can be concentrated to give alpha-tocotrienol quinone of highpurity.

In another embodiment, the foregoing quantities of alpha-tocotrienol oralpha-tocotrienol quinone can be produced using a single performance ofthe method, that is, with a single iteration of the steps of the method.

In some embodiments, as described in FIG. 3, the process comprises thesteps of:

3a.) reacting a plant extract mixture, comprising at least one non-alphatocotrienol, with suitable reagents which will react with the one ormore non-alpha-tocols to introduce a functional group in the free 5and/or 7 positions of the one or more non-alpha-tocols;

3b.) separating the one or more non-alpha-tocol homologues that havebeen functionalized, from the alpha-tocotrienol, the optional alphatocopherol and other non-tocol compounds that may be present;

3c.) optionally further separating the alpha-tocotrienol in the mixtureseparated in step (3b), from the optional alpha tocopherol and othernon-tocol compounds;

3d.) chemically reacting the one or more non-alpha-tocol functionalizedhomologues to give alpha-tocotrienol;

3e.) optionally combining the alpha-tocotrienol from step (3c) with thenewly produced alpha-tocotrienol from step (3d) to givealpha-tocotrienol of high purity; and

3f.) oxidizing the alpha-tocotrienol from step (3e) to givealpha-tocotrienol quinone of high purity.

In another embodiment, step 3b) is followed by an optional step 3b1) offiltering a solution of the one or more non-alpha-tocols homologues thathave been functionalized. Filtration can be performed using diatomaceousearth such as Celite® or any other method of filtration known to theskilled artisan.

In another embodiment, step 3d) is followed by an optional step 3d1),and/or step 3e) is followed by an optional step 3e1), wherein a solutionof the alpha-tocotrienol (in a solvent such as toluene) produced by thereduction is mixed with silica gel. The silica gel is removed byfiltration, and the remaining filtrate is concentrated to givealpha-tocotrienol of high purity.

In another embodiment, both steps 3b1) and 3d1), both steps 3b1) and3e1), or all three steps 3b1), 3d1), and 3e1) are performed.

In one embodiment, introduction of a functional group in the free 5and/or 7 positions of the non-alpha tocol homologues comprisesintroduction of a group which provides for increased differentialsolubility of the functionalized non-alpha tocol homologues compared tonon-functionalized compounds in the starting material, source material,or extract. The increased differential solubility can be differentialsolubility in a single solvent, or increased differential solubilitybetween two or more solvents in a mixed solvent system. In oneembodiment, the introduction of a functional group in the free 5 and/or7 positions of the non-alpha tocol homologues is accomplished withoutreducing the double bonds present in tocotrienol compounds and/orwithout causing isomerization of the double bonds present in tocotrienolcompounds. In one embodiment, the step of chemically reacting thenon-alpha tocol functionalized homologues to produce alpha-tocotrienolis accomplished without reducing the double bonds present in tocotrienolcompounds and/or without causing isomerization of the double bondspresent in tocotrienol compounds.

In one embodiment, the functionalization is introduced byamino-alkylation followed by acidification, thus converting thenon-alpha-tocotrienol into the corresponding amino-alkylated product andconverting said products to acid salts. In some embodiments, thefunctionalization is introduced by amino-alkylation with a formaldehydeequivalent, such as paraformaldehyde, and an amine, such as a secondaryamine, such as a cyclic amine such as 1-methylpiperazine, piperidine ormorpholine. In some embodiments, the functionalization is introduced byamino-alkylation with paraformaldehyde and 1-methylpiperazine. In someembodiments, the functionalization is introduced by amino-alkylationwith paraformaldehyde and morpholine.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol of high purity. In some embodiments, the purityis in the range of 80% to 99.9%, or in the range of 85% to 99.9%, or inthe range of 90% to 99.9%, or in the range of 95% to 99.9%. In someembodiments, the purity is in the range of about 80% to about 99.9%, orin the range of about 85% to about 99.9%, or in the range of about 90%to about 99.9%, or in the range of about 95% to about 99.9%. In someembodiments, the purity is more than 80%, or more than 85%, or more than90%, or more than 91%, or more than 92%, or more than 93%, or more than94%, or more than 95%, or more than 96%, or more than 97%, or more than98%, or more than 99%, or more than 99.5%, or more than 99.9%. In someembodiments, the purity is more than about 80%, or more than about 85%,or more than about 90%, or more than about 91%, or more than about 92%,or more than about 93%, or more than about 94%, or more than about 95%,or more than about 96%, or more than about 97%, or more than about 98%,or more than about 99%, or more than about 99.5%, or more than about99.9%. In other embodiments, the impurities in the final product areless than 20%, or less than 15%, or less than 10%, or less than 5%, orless than 4%, or less than 3%, or less than 2%, or less than 1%, or lessthan 0.5%, or less than 0.1%. In other embodiments, the impurities inthe final product are less than about 20%, or less than about 15%, orless than about 10%, or less than about 5%, or less than about 4%, orless than about 3%, or less than about 2%, or less than about 1%, orless than about 0.5%, or less than about 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5% or less than 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than about 5%, less than about 4%, less than about 3%,less than about 2%, less than about 1%, less than about 0.5% or lessthan about 0.1%. In one embodiment, the invention provides a method forlarge-scale production, enrichment, and/or isolation ofalpha-tocotrienol, such as quantities of material containingalpha-tocotrienol of at least 50 grams, at least 100 grams, at least 250grams, at least 500 grams, at least 1 kilogram, at least 2 kilograms, atleast 5 kilograms, or at least 10 kilograms, or at least about 50 grams,at least about 100 grams, at least about 250 grams, at least about 500grams, at least about 1 kilogram, at least about 2 kilograms, at leastabout 5 kilograms, or at least about 10 kilograms. The quantity ofmaterial containing alpha-tocotrienol can have any purity level asrecited herein.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol quinone of high purity. In some embodiments, thepurity is in the range of 80% to 99.9%, or in the range of 85% to 99.9%,or in the range of 90% to 99.9%, or in the range of 95% to 99.9%. Insome embodiments, the purity is in the range of about 80% to about99.9%, or in the range of about 85% to about 99.9%, or in the range ofabout 90% to about 99.9%, or in the range of about 95% to about 99.9%.In some embodiments, the purity is more than 80%, or more than 83%, ormore than 90%, or more than 91%, or more than 92%, or more than 93%, ormore than 94%, or more than 95%, or more than 96%, or more than 97%, ormore than 98%, or more than 99%, or more than 99.5%, or more than 99.9%.In some embodiments, the purity is more than about 80%, or more thanabout 85%, or more than about 90%, or more than about 91%, or more thanabout 92%, or more than about 93%, or more than about 94%, or more thanabout 95%, or more than about 96%, or more than about 97%, or more thanabout 98%, or more than about 99%, or more than about 99.5%, or morethan about 99.9%. In other embodiments, the impurities in the finalproduct are less than 20%, or less than 15%, or less than 10%, or lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1%, or less than 0.5%, or less than 0.1%. In other embodiments, theimpurities in the final product are less than about 20%, or less thanabout 15%, or less than about 10%, or less than about 5%, or less thanabout 4%, or less than about 3%, or less than about 2%, or less thanabout 1%, or less than about 0.5%, or less than about 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than 5%, less than 4%, less than 3%, lessthan 2%, less than 1%, less than 0.5% or less than 0.1%. In otherembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than about 5%, less than about 4%, less thanabout 3%, less than about 2%, less than about 1%, less than about 0.5%or less than about 0.1%. In one embodiment, the invention provides amethod for large-scale production, enrichment, and/or isolation ofalpha-tocotrienol quinone, such as quantities of material containingalpha-tocotrienol quinone of at least 50 grams, at least 100 grams, atleast 250 grams, at least 500 grams, at least 1 kilogram, at least 2kilograms, at least 5 kilograms, or at least 10 kilograms, or at leastabout 50 grams, at least about 100 grams, at least about 250 grams, atleast about 500 grams, at least about 1 kilogram, at least about 2kilograms, at least about 5 kilograms, or at least about 10 kilograms.The quantity of material containing alpha-tocotrienol quinone can haveany purity level as recited herein.

In one embodiment, the conversion of alpha-tocotrienol toalpha-tocotrienol quinone of step 3f) is carried out under bufferedconditions. In one embodiment, the buffer and/or base employed duringconversion of alpha-tocotrienol to alpha-tocotrienol quinone of step 3f)is sodium carbonate, sodium hydrogen carbonate, potassium carbonate,potassium hydrogen carbonate, phosphate buffer, or any mixture in anyproportion of two or more of the foregoing buffers.

In another embodiment, the invention comprises a method for oxidizingalpha-tocotrienol to alpha-tocotrienol quinone with minimalisomerization of the double bonds of the triene moiety. In someembodiments, the alpha-tocotrienol quinone,2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione,produced by the method comprises at least about 80%, at least about 90%,at least about 95%, at least about 96%, at least about 97%, at leastabout 98%, at least about 99%, at least about 99.5%, or at least about99.9% of the2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dionematerial present.

In any of the above embodiments, the oxidation of alpha-tocotrienol toalpha-tocotrienol quinone can be performed with cerium (IV) ammoniumnitrate.

In another embodiment, a solution of alpha-tocotrienol quinone, in asolvent such as isopropylacetate, n-heptane, or a mixture ofisopropylacetate and n-heptane, is placed on a chromatography columnpacked with silica gel. The silica gel can contain between about 0.1-5%by weight of sodium hydrogen carbonate, such as about 0.5-2% by weightor about 1% by weight of sodium hydrogen carbonate. Thealpha-tocotrienol quinone can be eluted from the silica gel/NaHCO₃ withsolvents, such as n-heptane, isopropylacetate, orn-heptane:isopropylacetate in ratios of about 100:1, about 100:5, about100:10, or about 100:15. The recovered solution of alpha-tocotrienolquinone can be concentrated to give alpha-tocotrienol quinone of highpurity.

In another embodiment, the foregoing quantities of alpha-tocotrienol oralpha-tocotrienol quinone can be produced using a single performance ofthe method, that is, with a single iteration of the steps of the method.

In some embodiments, as described in FIG. 4, the process comprises thesteps of:

4a.) reacting a palm oil extract mixture, comprising at least onenon-alpha tocotrienol, with amino-alkylating agents which will reactwith the one or more non-alpha-tocols to introduce a functional group inthe free 5 and/or 7 positions of the one or more non-alpha-tocotrienolsand converting the products into acid salts;

4b.) separating the one or more non-alpha-tocotrienol acid salts of theproducts (from step 4a) from the alpha-tocotrienol, optional alphatocopherol and other non-tocol compounds that may be present;

4c.) reducing the one or more non-alpha-tocotrienol functionalizedhomologues (from step 4b) with a reducing agent to givealpha-tocotrienol of high purity; and

4d.) oxidizing the alpha-tocotrienol from step (4c) to givealpha-tocotrienol quinone of high purity.

In another embodiment, step 4b) is followed by an optional step 4b1) offiltering a solution of the one or more non-alpha-tocols homologues thathave been functionalized. Filtration can be performed using diatomaceousearth such as Celite® or any other method of filtration known to theskilled artisan.

In another embodiment, step 4c) is followed by an optional step 4c1),wherein a solution of the alpha-tocotrienol (in a solvent such astoluene) produced by the reduction is mixed with silica gel. The silicagel is removed by filtration, and the remaining filtrate is concentratedto give alpha-tocotrienol of high purity.

In another embodiment, both steps 4b1) and 4c1) are performed.

In one embodiment, the conversion of alpha-tocotrienol toalpha-tocotrienol quinone of step 4d) is carried out under bufferedconditions. In one embodiment, the buffer and/or base employed duringconversion of alpha-tocotrienol to alpha-tocotrienol quinone of step 4d)is sodium carbonate, sodium hydrogen carbonate, potassium carbonate,potassium hydrogen carbonate, phosphate buffer, or any mixture in anyproportion of two or more of the foregoing buffers.

In one embodiment, introduction of an aminoalkyl group in the free 5and/or 7 positions of the non-alpha tocol homologues provides forincreased differential solubility of the functionalized non-alpha tocolhomologues compared to non-functionalized compounds in the startingmaterial, source material, or extract. The increased differentialsolubility can be differential solubility in a single solvent, orincreased differential solubility between two or more solvents in amixed solvent system. In one embodiment, the introduction of anaminoalkyl group in the free 5 and/or 7 positions of the non-alpha tocolhomologues is accomplished without reducing the double bonds present intocotrienol compounds and/or without causing isomerization of the doublebonds present in tocotrienol compounds. In one embodiment, the step ofreducing the non-alpha tocol functionalized homologues to producealpha-tocotrienol is accomplished without reducing the double bondspresent in tocotrienol compounds and/or without causing isomerization ofthe double bonds present in tocotrienol compounds.

In another embodiment, the amino-alkylation is performed with aformaldehyde equivalent, such as paraformaldehyde, and an amine, such asa secondary amine, such as a cyclic amine selected from1-methylpiperazine, piperidine or morpholine. In yet another embodimentthe amino-alkylation is performed with paraformaldehyde and1-methylpiperazine. In yet another embodiment, the amino-alkylation isperformed with paraformaldehyde and morpholine.

In another embodiment, a solution of alpha-tocotrienol quinone, in asolvent such as isopropylacetate, n-heptane, or a mixture ofisopropylacetate and n-heptane, is placed on a chromatography columnpacked with silica gel. The silica gel can contain between about 0.1-5%by weight of sodium hydrogen carbonate, such as about 0.5-2% by weightor about 1% by weight of sodium hydrogen carbonate. Thealpha-tocotrienol quinone can be eluted from the silica gel/NaHCO₃ withsolvents, such as n-heptane, isopropylacetate, orn-heptane:isopropylacetate in ratios of about 100:1, about 100:5, about100:10, or about 100:15. The recovered solution of alpha-tocotrienolquinone can be concentrated to give alpha-tocotrienol quinone of highpurity.

In any of the embodiments above, the processes of the invention canyield alpha-tocotrienol of high purity. In some embodiments, the purityis in the range of 80% to 99.9%, or in the range of 85% to 99.9%, or inthe range of 90% to 99.9%, or in the range of 95% to 99.9%. In someembodiments, the purity is in the range of about 80% to about 99.9%, orin the range of about 85% to about 99.9%, or in the range of about 90%to about 99.9%, or in the range of about 95% to about 99.9%. In someembodiments, the purity is more than 80%, or more than 85%, or more than90%, or more than 91%, or more than 92%, or more than 93%, or more than94%, or more than 95%, or more than 96%, or more than 97%, or more than98%, or more than 99%, or more than 99.5%, or more than 99.9%. In someembodiments, the purity is more than about 80%, or more than about 85%,or more than about 90%, or more than about 91%, or more than about 92%,or more than about 93%, or more than about 94%, or more than about 95%,or more than about 96%, or more than about 97%, or more than about 98%,or more than about 99%, or more than about 99.5%, or more than about99.9%. In other embodiments, the impurities in the final product areless than 20%, or less than 15%, or less than 10%, or less than 5% orless than 4%, or less than 3%, or less than 2%, or less than 1%, or lessthan 0.5%, or less than 0.1%. In other embodiments, the impurities inthe final product are less than about 20%, or less than about 15%, orless than about 10%, or less than about 5%, or less than about 4%, orless than about 3%, or less than about 2%, or less than about 1%, orless than about 0.5%, or less than about 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than 5%, less than 4%, less than 3%, less than 2%, lessthan 1%, less than 0.5% or less than 0.1%. In other embodiments, theimpurities consisting of tocols or tocol derivatives in the finalproduct are less than about 5%, less than about 4%, less than about 3%,less than about 2%, less than about 1%, less than about 0.5% or lessthan about 0.1%. In one embodiment, the invention provides a method forlarge-scale production, enrichment, and/or isolation ofalpha-tocotrienol, such as quantities of material containingalpha-tocotrienol of at least 50 grams, at least 100 grams, at least 250grams, at least 500 grams, at least 1 kilogram, at least 2 kilograms, atleast 3 kilograms, or at least 10 kilograms, or at least about 50 grams,at least about 100 grams, at least about 250 grams, at least about 500grams, at least about 1 kilogram, at least about 2 kilograms, at leastabout 5 kilograms, or at least about 10 kilograms. The quantity ofmaterial containing alpha-tocotrienol can have any purity level asrecited herein.

In any of the processes for the production of alpha-tocotrienol quinonedescribed above, the alpha-tocotrienol quinone is of high purity. Insome processes, the purity is in the range of 80% to 99%, or in therange of 85% to 99% or in the range of 90% to 99%, or in the range of95% to 99%. In some processes, the purity is more than 80%, or more than85%, more than 90%, or more than 91%, or more than 92%, or more than93%, or more than 94%, or more than 95%, or more than 96%, or more than97%, or more than 98%, or more than 99%, or more than 99.5%, or morethan 99.9%. In other embodiments, the impurities in the final productare less than 20%, or less than 15%, or less than 10%, or less than 5%,or less than 4%, or less than 3%, or less than 2%, or less than 1%, orless than 0.5%, or less than 0.1%. In some embodiments, the impuritiesconsisting of tocols or tocol derivatives in the final product are lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1%, or less than 0.5%, or less than 0.1%. In some processes, the purityis in the range of about 80% to about 99%, or in the range of about 85%to about 99% or in the range of about 90% to about 99%, or in the rangeof about 95% to about 99%. In some processes, the purity is more thanabout 80%, or more than about 83%, more than about 90%, or more thanabout 91%, or more than about 92%, or more than about 93%, or more thanabout 94%, or more than about 95%, or more than about 96%, or more thanabout 97%, or more than about 98%, or more than about 99%, or more thanabout 99.5%, or more than about 99.9%. In other embodiments, theimpurities in the final product are less than about 20%, or less thanabout 15%, or less than about 10%, or less than about 5%, or less thanabout 4%, or less than about 3%, or less than about 2%, or less thanabout 1%, or less than about 0.5%, or less than about 0.1%. In someembodiments, the impurities consisting of tocols or tocol derivatives inthe final product are less than about 5%, or less than about 4%, or lessthan about 3%, or less than about 2%, or less than about 1%, or lessthan about 0.5%, or less than about 0.1%.

In another embodiment, the invention comprises a method for oxidizingalpha-tocotrienol to alpha-tocotrienol quinone with minimalisomerization of the double bonds of the triene moiety. In someembodiments, the alpha-tocotrienol quinone,2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione,produced by the method comprises at least about 80%, at least about 90%,at least about 95%, at least about 96%, at least about 97%, at leastabout 98%, at least about 99%, at least about 99.5%, or at least about99.9% of the2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dionematerial present.

In any of the embodiments recited above, the non-alpha tocols can bereacted with a formaldehyde equivalent and at least one amine compoundof the formula H—N(R₁₁)(R₁₂), where R₁₁ and R₁₂ are independentlyselected from the group consisting of H and C₁-C₈ alkyl or where R₁₁ andR₁₂ are combined together with the nitrogen to which they are bonded toform a five-to-eight membered heterocyclic ring, said heterocyclic ringhaving zero, one, or two additional heteroatoms in addition to thenitrogen to which R₁₁ and R₁₂ are bonded.

In any of the above embodiments, the oxidation of alpha-tocotrienol toalpha-tocotrienol quinone can be performed with cerium (IV) ammoniumnitrate.

In another embodiment, the quantities of alpha-tocotrienol oralpha-tocotrienol quinone described herein, at any level of puritydescribed herein, can be produced using a single performance of a methodrecited herein, that is, with a single iteration of the steps of themethod.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart depicting certain processes of the invention.

FIG. 2 is a flow chart depicting additional processes of the invention.

FIG. 3 is a flow chart depicting additional processes of the invention.

FIG. 4 is a flow chart depicting additional processes of the invention.

METHODS FOR CARRYING OUT THE INVENTION

The invention embraces a method for production, enrichment and/orisolation of pure alpha-tocotrienol from natural extracts that comprisemixed tocotrienols.

The term “tocols” refers to tocopherols and tocotrienols as describedherein.

The term “non-tocols” refers to phytonutrients or organic materials thatmay be present in the extract, but are not tocopherols or tocotrienols.

The term “amino-alkylation,” also known as the Mannich reaction, is areaction that effects amino-alkyl addition. The reaction can beconducted from at about room temperature up to about 140° C. for asufficient length of time to effectuate amino-alkylation. The reagentsnecessary are a source of formaldehyde (a “formaldehyde equivalent”) andan amine. Any primary or secondary amine, including amines such ascyclic and aromatic amines, alkyl amines, and polyamines, as well asammonia, can be used. Particular examples of suitable amines are dibutylamine, di-isopropyl amine, dimethyl amine, diethyl amine, dipropylamine, 1-methylpiperazine, N,N,N′-trimethylethylenediamine, piperidine,pyrrolidine and morpholine. Sources of formaldehyde (i.e., formaldehydeequivalents) include, but are not limited to, paraformaldehyde,formaline, formaldehyde gas, trioxane and hexamethylenetetramine. Therelative molar concentration of the formaldehyde equivalent and theamine are maintained in equimolar amounts, but the relativeconcentrations may be varied as long as there is at least one mole ofamine and at least one mole of formaldehyde for every mole of freearomatic position on the tocotrienols, and, if present, any othercompounds that will react with the formaldehyde and amine reagents.Either the amine or formaldehyde component may be present in an amountof from about 1 to about 20 moles per mole of free aromatic position ontocotrienol, and, if present, any other compounds that will react withthe formaldehyde and amine reagents, particularly in a molar amount ofat least about four times greater than the free aromatic positions ontocotrienol present, and, if present, any other compounds that willreact with the formaldehyde and amine reagents. This process could alsobe accomplished step-wise, for example by formylation followed byreductive amination, or by pre-formation of the “Mannich” reagent—thealkyliminium or functional equivalent intermediate.

The starting material is a mixed tocotrienol extract that may alsooptionally comprise alpha tocopherol in amounts that may vary dependingon the source of the extract. Naturally produced alpha-tocotrienol andoptional alpha tocopherol are separated from the beta, gamma, anddelta-tocotrienol homologues of alpha-tocotrienol, by reacting themixture of tocotrienols and optional alpha tocopherol with anappropriate reagent or reagents to introduce a functional group at thefree 5 and/or 7 positions of the non-alpha-tocotrienols. For example,the starting material can be amino-alkylated to introduceamino-alkylated groups on the beta, gamma, and delta-tocotrienols. Asalpha-tocotrienol does not have a free ring position, anyalpha-tocotrienol present in the mixture will not be amino-alkylated.The amino-alkylated groups will allow the separation of theamino-alkylated beta, gamma, and delta-tocotrienols fromalpha-tocotrienol, alpha tocopherol and other non-tocol phytonutrientsthat may be present. The separation will be accomplished by partitioningbetween different organic solvents. Any non-polar organic solvents suchas hexanes, heptanes, pentanes, petroleum ether, or mixtures thereof,can be used to take up the alpha tocopherol, alpha-tocotrienol and otherphytonutrients or hydrocarbon impurities. The amino-alkylated products,optionally having been converted to an acid salt, can be partitioned inan acidic organic layer such as acetonitrile comprising formic acid. Inanother embodiment of the invention, the partitioning can be performedbetween an organic layer and an aqueous layer. Alternatively, theproducts from the amino-alkylation can be removed by firstpermethylating to the tetra alkyl ammonium salt, followed by reductivedeamination under basic conditions (see for example Maeda, Y. et al.,JOC (1994) 59, 7897-7901; and Tayama, E. et al, Chem Letters (2006) 35,478-479).

By the term “reducing agent” is contemplated hydrides such as lithiumaluminum hydride, sodium borohydride, and sodium cyano borohydride,borane complexes and electron donors such as sodium, lithium, magnesium,potassium, zinc, nickel, or amalgams thereof in the presence of asuitable proton source such as ammonium salts or carboxylic acids.

The phrase “impurities consisting of tocols or tocol derivatives in thefinal product” refers to beta-tocotrienol, gamma-tocotrienol,delta-tocotrienol, alpha-tocopherol, beta-tocopherol, gamma-tocopherol,or delta-tocopherol. Reference to “impurities” in the final product,without further specification, can refer to beta-tocotrienol,gamma-tocotrienol, delta-tocotrienol, alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, and/or other non-tocol impurities.In one embodiment, solvents which can be readily removed by evaporationare not considered as impurities when determining the percentage ofimpurities present.

The quinone (cyclohexadienedione) form and dihydroquinone (benzenediol)form of the compounds disclosed herein are readily interconverted withappropriate reagents. The quinone can be treated in a biphasic mixtureof an ethereal solvent with a basic aqueous solution of Na₂S₂O₄ (Vogel,A. I. et al. Vogel's Textbook of Practical Organic Chemistry, 5^(th)Edition, Prentice Hall: New York, 1996; Section 9.6.14 Quinones,“Reduction to the Hydroquinone”). Standard workup in the absence ofoxygen yields the desired hydroquinone. The hydroquinone form can beoxidized to the quinone form with oxidizing agents such as cericammonium nitrate (CAN) or ferric chloride. The quinone and hydroquinoneforms are also readily interconverted electrochemically, as is wellknown in the art. See, e.g., Section 33.4 of Streitweiser & Heathcock,Introduction to Organic Chemistry, New York: Macmillan, 1976.

Because reaction of alpha-tocopherol with cerium (IV) ammonium nitrategenerates nitric acid, the oxidation can be carried out under bufferedconditions. This can be accomplished by including sodium carbonate,sodium hydrogen carbonate, other carbonates such as potassium carbonateor potassium hydrogen carbonate, phosphate buffers, other buffers, ormatures of any two or more of the foregoing buffers in any proportion,during the oxidation. Removal of acid during oxidation reducesisomerization of the double bonds in the triene moiety of thetocotrienol and tocotrienol quinone. Buffered conditions can also bemaintained during workup of the alpha-tocotrienol quinone, for example,by mixing a percentage of a solid buffer such as sodium hydrogencarbonate with silica gel prior to placing the alpha-tocotrienol on thesilica gel for elution.

When silica gel is used in the workup, the grade of silica gel used canbe that used for standard preparative flash chromatography. For example,silica gel of about 60 Å pore size with a particle distribution of about40 to 63 microns can be used. It can be used as is from the supplier,without further activation, or can be activated by heating in air or anoxygen-containing atmosphere.

This invention is further illustrated by the following example of apreferred embodiment thereof. This example is included merely forpurposes of illustration and is not intended to limit the scope of theinvention.

EXAMPLE

General Procedures

All solvents and reagents were used as obtained from their respectivesuppliers except as noted. ¹H and ¹³C NMR were obtained on a VarianUltrashielded magnet at 400 MHz and 100 MHz respectively in deuteratedsolvents as noted. All spectra are referenced in ppm to either theirresidual solvent peak, as defined in Gottlieb, H. E. et al.; J. Org.Chem. 1997, 62, 7512-7515, or TMS at 0.00 ppm.

EXPERIMENTALS Step 1-Aminomethylation

To Tocomin™-50 (1.0 wt,) was added paraformaldehyde (0.08 wt, 95%) and1-Methylpiperazine (0.3 vol). Use suspension was stirred at roomtemperature for 30 min, and then at 75° C. for 2 to 3 h. The solutionwas heated at 125° C. and monitored for conversion of starting materialcomponents to product components. The mixture was cooled to 30 to 40°C., diluted with acetonitrile (3.5 mL/g) and heptane (3.5 mL/g), andthen cooled to 5° C., and treated dropwise with formic acid (1.0 vol).The bottom acetonitrile layer was separated and extracted with heptane(2×3.5 mL/g). The acetonitrile layer was diluted with tert-butyl methylether (3 mL/g) and cooled to 0° C. 45% w/w aqueous tribasic potassiumphosphate solution (7 mL/g) was added dropwise (exothermic) so as tokeep the temperature below 20° C. The organic layer was separated atroom temperature, washed with saturated aqueous sodium chloride solution(23.1% w/w; 3 mL/g), and solvents were removed by distillation at up to50° C. under vacuum. To the concentrated solution was added toluene (5mL/g). Solvent (5 mL/g) was removed by distillation at up to 50° C.under vacuum. To the solution was added additional toluene (5 mL/g).Solvent (5 mL/g) was removed by distillation at up to 50° C. undervacuum. The residue was diluted with toluene (1.5 mL/g) and filteredthrough a pad of Celite™ packed from a suspension in toluene. TheCelite™ cake was washed with toluene (1 mL/g). All filtrates werecombined. The reaction mass yield was determined by loss-on-dryinganalysis of an aliquot of the reaction mixture. The solvents wereremoved by distillation at up to 50° C. under vacuum. The concentratedsolution of product aminomethylated tocols was used, as is, in Step 2.

Step 2-Reduction

Note: unless otherwise indicated, all relative weight (wt) and volume(mL/g) equivalents in Step 2 are with respect to the loss on dryingfigure determined at the end of Stage 1.

To the residue prepared in Step 1 was added toluene (8 vol). A solventexchange to a solution in 3-methylbutanol (3.0 vol) was then prepared bydistillation at up to 50° C. under vacuum, with additions of3-methylbutanol.

To sodium cyanoborohydride (0.43 wt) was added 3-methylbutanol (2 vol)at room temperature. The suspension was stirred at room temperature for30 min, and then heated to 125° C. To this preheated mixture was addedover 1.5 h the previously prepared solution of aminomethylated tocols in3-methylbutanol (3.0 vol) followed by an additional rinse of3-methylbutanol (0.5 vol). The mixture was heated at 125° C. andmonitored for conversion of starting material components to productcomponents.

The mixture was cooled to 50° C., diluted with heptane (5 vol), thencooled to 0° C., and treated with 45% w/w aqueous tribasic potassiumphosphate solution (5.0 vol) (exothermic, gas evolution) so as tomaintain a temperature below 25° C. The two-phase mixture was stirred atroom temperature for 2 h, the organic layer was separated, washed with45% w/w aqueous tribasic potassium phosphate solution (3 vol), andconcentrated by distillation at up to 50° C. under vacuum. To theresidue was added toluene (7 vol). The resulting solution was added to amixture of silica gel (2 wt) and toluene (5.5 vol) with an additionalrinse of toluene (2 vol). The silica gel suspension was stirred at roomtemperature for 1 h. The silica gel was removed by filtration and washedwith toluene (2×5 vol). The combined filtrates were concentrated bydistillation at up to 50° C. under vacuum. The residue solution wascooled to 30° C. and transferred to a rotoevaporator with toluene (2×1.4vol) and further evaporated to dryness by distillation at up to 60° C.under vacuum to give alpha-tocotrienol. ¹H-NMR (400 MHz,CDCl₃)=5.17-5.05 (m, 3H), 4.16 (s, 1H), 2.61 (t, J=6.8 Hz, 2H),2.16-2.01 (m, 6H), 2.16 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.01-1.93(m, 4H), 1.87-1.73 (m, 2H), 1.68-1.49 (m, 2H), 1.68 (s, 3H), 1.60 (s,6H), 1.58 (s, 3H), 1.25 (s, 3H).

Step 3-Chroman to Quinone Oxidation

Note: unless otherwise indicated all relative weight (wt) and volume(mL/g) equivalents in Step 3 are with respect to the mass of thisstage's starting material, the product of Step 2—alpha-tocotrienol.

The residue of Step 2 was dissolved in isopropyl acetate (10 vol), water(0.5 vol) was added, and the mixture was cooled to 0° C. A solution ofcerium (IV) ammonium nitrate (2.74 wt) in water (3 vol) was prepared atroom temperature and buffered by addition of saturated aqueous sodiumcarbonate solution (17.4% w/w; 0.75 vol). The buffered cerium (IV)ammonium nitrate solution was added over 30 min to the prepared mixtureof alpha-tocotrienol from step 2 in isopropylacetate and water whilemaintaining the temperature at 0° C. The mixture was stirred at 0° C.and monitored for conversion of starting material components to productcomponents. The organic layer was separated and treated for 2 h with aslurry of solid sodium hydrogen carbonate (2 wt) and solid sodiumsulfate (2 wt) in isopropylacetate (5 vol). The suspension was filtered,the solids washed with isopropylacetate (1.5 vol), and the combinedfiltrates treated with sodium hydrogen carbonate (2×0.05 wt). Thesuspension was concentrated to a maximum extent while maintaining anagitable mixture by distillation at up to 45° C. under vacuum. Theresidue was cooled to 30° C. and diluted with n-heptane (10 vol). Achromatography column of silica gel (5 wt) and sodium hydrogen carbonate(0.05 wt) was prepared from a slurry in n-heptane. The mixture waseluted on the chromatography column and further eluted with mixtures ofn-heptane/isopropylacetate in relative volume-ratios of 100:5 and then100:10. Fractions were collected, treated with solid sodium hydrogencarbonate (ca. 0.1 to 1 g/L eluent), and analyzed for product contentand purity. Acceptable fractions were combined, treated with additionalsolid sodium hydrogen carbonate (0.05 wt), and concentrated to a maximumextent while maintaining an agitable mixture by distillation of solventat up to 45° C. under vacuum. Isopropylacetate (1 to 3 vol) was addedand the mixture passed through a 0.45 to 1 um filter. The filtrate wasevaporated to dryness by distillation of solvent at up to 40° C. undervacuum to give the product, alpha-tocotrienol quinone. ¹H-NMR (400 MHz,C₆D₆) 5.37-5.28 (t br m, J=7 Hz, 2H), 5.28-5.20 (t br m, J=6 Hz, 1H),2.53-2.46 (m, 2H), 2.25-2.15 (m, 6H), 2.15-2.07 (m, 4H) 1.91 (s, 3H),1.73-1.71 (br d, J=1 Hz, 3H), 1.71-1.70 (br d, J=1 Hz, 3H, 1.68 (s, 6H),1.62 (s, 3H), 1.57 (s, 3H), 1.54-1.47 (m, 2H), 1.47-1.40 (ddd, J=8.6, 1Hz, 2H), 1.10 (s, 3H), 1.00 (s, 1H).

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein by an identifyingcitation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A process for the production, enrichment and/orisolation of alpha-tocotrienol from a plant extract that comprises atleast one non-alpha tocotrienol and that optionally comprisesalpha-tocotrienol, optionally comprises alpha-tocopherol and optionallycomprises other tocols, non-tocols and/or organic impurities, comprisingthe steps of: 1a.) reacting the plant extract with suitable reagentswhich react with the one or more non-alpha-tocols to introduce afunctional group in the free 5 and/or 7 position of the one or morenon-alpha-tocols; 1b.) separating the one or more non-alpha-tocols thathave been functionalized in step (1a) from the optionalalpha-tocotrienol and optional alpha tocopherol and optional non-tocolcompounds that may be present; 1c.) optionally further separating thealpha-tocotrienol in the mixture separated in step (1b), from theoptional alpha tocopherol and from optional non-tocols; 1d.) chemicallyreacting the separated one or more non-alpha-tocols that have beenfunctionalized from step (1b) to give alpha-tocotrienol; and 1e.)optionally combining the alpha-tocotrienol from step (1c) with thealpha-tocotrienol from step (1d) to give alpha-tocotrienol, wherein step1a.) comprises amino-alkylation performed with a formaldehyde equivalentand 1-methylpiperazine, followed by acidification; and wherein step 1d.)comprises reduction performed with sodium cyano borohydride.
 2. Theprocess of claim 1, wherein the plant extract is selected from the groupconsisting of a palm oil extract, a palm fruit extract, a rice extract,a rice bran extract, a barley extract, an annatto extract, and a mixturethereof.
 3. The process of claim 2, wherein the plant extract is a palmoil extract.
 4. The process of claim 2, wherein the plant extract isTocomin®.
 5. The process of claim 1, additionally comprising anadditional last step wherein the alpha-tocotrienol (from steps 1d and/or1e) is oxidized to alpha-tocotrienol quinone.
 6. The process of claim 3,additionally comprising an additional last step wherein thealpha-tocotrienol (from steps 1d and/or 1e) is oxidized toalpha-tocotrienol quinone.
 7. The process of claim 1, additionallycomprising a step 1b1) after step 1b), wherein a solution of thenon-alpha-tocols that have been functionalized is filtered.
 8. Theprocess of claim 1, additionally comprising a step 1d1) after step 1d)wherein a solution of the alpha-tocotrienol produced in step 1d) ismixed with silica gel, followed by removal of the silica gel byfiltration.
 9. The process of claim 1, where the formaldehyde equivalentis paraformaldehyde.
 10. The process of claim 1, wherein step 1d) isperformed in the presence of 3-methylbutanol solvent.
 11. The process ofclaim 1, wherein the formaldehyde equivalent is paraformaldehyde, andwherein step 1d) is performed in the presence of 3-methylbutanolsolvent.
 12. A compound selected from the group consisting of:

or an acid salt thereof; or a tetra alkyl ammonium salt thereof.
 13. Thecompound of claim 12, wherein the compound is selected from the groupconsisting of:


14. The compound of claim 12, wherein the compound is an acid saltthereof.
 15. The compound of claim 14, wherein the acid salt is a formicacid salt.
 16. The compound of claim 12, wherein the compound is atetra-alkyl ammonium salt thereof.